Border-associated macrophages mediate the neuroinflammatory response in an alpha-synuclein model of Parkinson disease.

Dopaminergic cell loss due to the accumulation of α-syn is a core feature of the pathogenesis of Parkinson disease. Neuroinflammation specifically induced by α-synuclein has been shown to exacerbate neurodegeneration, yet the role of central nervous system (CNS) resident macrophages in this process remains unclear. We found that a specific subset of CNS resident macrophages, border-associated macrophages (BAMs), play an essential role in mediating α-synuclein related neuroinflammation due to their unique role as the antigen presenting cells necessary to initiate a CD4 T cell response whereas the loss of MHCII antigen presentation on microglia had no effect on neuroinflammation. Furthermore, α-synuclein expression led to an expansion in border-associated macrophage numbers and a unique damage-associated activation state. Through a combinatorial approach of single-cell RNA sequencing and depletion experiments, we found that border-associated macrophages played an essential role in immune cell recruitment, infiltration, and antigen presentation. Furthermore, border-associated macrophages were identified in post-mortem PD brain in close proximity to T cells. These results point to a role for border-associated macrophages in mediating the pathogenesis of Parkinson disease through their role in the orchestration of the α-synuclein-mediated neuroinflammatory response.

A Comparison of Different Operating Systems for Femtosecond Lasers in Cataract Surgery.

The introduction of femtosecond lasers is potentially a major shift in the way we approach cataract surgery. The development of increasingly sophisticated intraocular lenses (IOLs), coupled with heightened patient expectation of high quality postsurgical visual outcomes, has generated the need for a more precise, highly reproducible and standardized method to carry out cataract operations. As femtosecond laser-assisted cataract surgery (FLACS) becomes more commonplace in surgical centers, further evaluation of the potential risks and benefits needs to be established, particularly in the medium/long term effects. Healthcare administrators will also have to weigh and balance out the financial costs of these lasers relative to the advantages they put forth. In this review, we provide an operational overview of three of five femtosecond laser platforms that are currently commercially available: the Catalys (USA), the Victus (USA), and the LDV Z8 (Switzerland).

Comparison of intra-ocular pressure changes with liquid or flat applanation interfaces in a femtosecond laser platform.

Cataract surgery is the most common surgical procedure and femtosecond laser assisted cataract surgery (FLACS) has gained increased popularity. FLACS requires the application of a suction device to stabilize the laser head and focus the laser beam accurately. This may cause a significant escalation in intra-ocular pressure (IOP), which poses potential risks for patients undergoing cataract surgery. In this study we aimed to assess the effect of the Ziemer LDV Z8 femtosecond cataract machine on IOP. We demonstrated through a porcine model that IOP was significantly higher with a flat interface but could be abrogated by reducing surgical compression and vacuum. Pressure was lower with a liquid interface, and further altering angulation of the laser arm could reduce the IOP to 36 mmHg. A pilot series in patients showed comparable pressure rises with the porcine model (30 mmHg). These strategies may improve the safety profile in patients vulnerable to high pressure when employing FLACS with the Ziemer LDV Z8.

Transmission of megawatt relativistic electron beams through millimeter apertures.

High-power, relativistic electron beams from energy-recovering linacs have great potential to realize new experimental paradigms for pioneering innovation in fundamental and applied research. A major design consideration for this new generation of experimental capabilities is the understanding of the halo associated with these bright, intense beams. In this Letter, we report on measurements performed using the 100 MeV, 430 kW cw electron beam from the energy-recovering linac at the Jefferson Laboratory's Free Electron Laser facility as it traversed a set of small apertures in a 127 mm long aluminum block. Thermal measurements of the block together with neutron measurements near the beam-target interaction point yielded a consistent understanding of the beam losses. These were determined to be 3 ppm through a 2 mm diameter aperture and were maintained during a 7 h continuous run.

Incidence, presenting features, and diagnosis of cicatrising conjunctivitis in the United Kingdom.

PURPOSE: Cicatrising conjunctival disorders are uncommon, and are difficult to diagnose and manage. This study was designed to assess the annual incidence and underlying diagnosis of patients with cicatrising conjunctivitis (CC) within the United Kingdom. METHODS: Clinical data of newly diagnosed cases of CC were reported via the British Ophthalmological Surveillance Unit at diagnosis and at 12 months follow-up. RESULTS: A total of 50 (61%) ocular mucous membrane pemphigoid (OcMMP), 16 (20%) Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS-TEN) and 16 (20%) other causes of CC, equating to an incidence of 0.8, 0.2, and 0.2 per million, respectively, were reported. Although diagnosis of SJS-TEN was usually within a median of 7 days of symptom-onset, that for OcMMP and other CC was a median 225 days for both. At diagnosis, 64/163 (39%) eyes had moderate/severe conjunctival inflammation, and 102/164 (62%) had symblepharon formation. Although 43/82 (52%) patients were commenced on immunosuppression or had this therapy modified, at follow-up there was an increase in the number of symblepharon, despite control of inflammation (P<0.001). Mortality only occurred in the SJS-TEN group (4/16 (25%)). CONCLUSION: CC has a substantial morbidity and for non-SJS-TEN causes, diagnosis is frequently delayed. The proportion of patients given immunosuppressive therapy to prevent disease progression may be less than optimal. These data highlight the need for developing patient access to specialist-designated centres with expertise in CC.

Evaluation of early and late presentation of patients with ocular mucous membrane pemphigoid to two major tertiary referral hospitals in the United Kingdom.

PURPOSE: Ocular mucous membrane pemphigoid (OcMMP) is a sight-threatening autoimmune disease in which referral to specialists units for further management is a common practise. This study aims to describe referral patterns, disease phenotype and management strategies in patients who present with either early or established disease to two large tertiary care hospitals in the United Kingdom. PATIENTS AND METHODS: In all, 54 consecutive patients with a documented history of OcMMP were followed for 24 months. Two groups were defined: (i) early-onset disease (EOD:<3 years, n=26, 51 eyes) and (ii) established disease (EstD:>5 years, n=24, 48 eyes). Data were captured at first clinic visit, and at 12 and 24 months follow-up. Information regarding duration, activity and stage of disease, visual acuity (VA), therapeutic strategies and clinical outcome were analysed. RESULTS: Patients with EOD were younger and had more severe conjunctival inflammation (76% of inflamed eyes) than the EstD group, who had poorer VA (26.7%=VA<3/60, P<0.01) and more advanced disease. Although 40% of patients were on existing immunosuppression, 48% required initiation or switch to more potent immunotherapy. In all, 28% (14) were referred back to the originating hospitals for continued care. Although inflammation had resolved in 78% (60/77) at 12 months, persistence of inflammation and progression did not differ between the two phenotypes. Importantly, 42% demonstrated disease progression in the absence of clinically detectable inflammation. CONCLUSIONS: These data highlight that irrespective of OcMMP phenotype, initiation or escalation of potent immunosuppression is required at tertiary hospitals. Moreover, the conjunctival scarring progresses even when the eye remains clinically quiescent. Early referral to tertiary centres is recommended to optimise immunosuppression and limit long-term ocular damage.

Calculations of synchrotron radiation emission in the transverse coherent limit.

We present approximations for the synchrotron radiation emission for low emittance light sources, which provide a connection between user needs and the electron beam parameters. The results and calculations are a consequence of the phase coherence in the emission from the electrons. We derive the remarkable result that if the electron beam is energetic enough, the emitted flux is independent of the photon energy, electron beam energy, or bending radius in the transverse coherent limit. Similarly the brightness is identical for all machines at a given current.

Early pathological features of the cornea in toxic epidermal necrolysis.

AIM: To describe the early pathological changes in the cornea during toxic epidermal necrolysis (TEN). METHOD: Demonstration of histological features of sequential corneal samples taken during management of complications of TEN in a young adult. RESULTS: Early vacuolation of basal keratinocytes and late infiltration of the cornea with CD 8 lymphocytes were observed. These changes are similar to those found in cutaneous TEN and may represent weakening of the stromal-epithelium interface with resultant recurrent erosion and chronic inflammation. CONCLUSIONS: Similar changes were found in avascular corneal tissue to those previously described in skin. The initial insult may be traumatic. We propose that a cytokine-mediated response contributes to the initial insult, either in response to and/or by accelerating severe inflammation. This precedes a cytotoxic infiltration which may exacerbate episodes of recurrent erosion. This provides a new insight into the mechanism of disease in the cornea following TEN.

Quality of life and visual rehabilitation: an observational study of low vision in three general practices in West Glamorgan.

AIM: To survey low vision in an urban population and assess impact on quality of life, rehabilitation and support. METHODS: In a cross-sectional population survey, 66 patients were identified from databases of three general practices and surveyed by investigator administered questionnaire. Main outcome measures were ocular diagnoses, (US) National Eye Institute Visual Function-Questionnaire (NEI-VFQ) scores assessing visual and nonvisual disability, eligibility for, awareness and receipt of rehabilitation and support. RESULTS: Of 24,420 individuals on the lists of the three study practices, we found 101 registered as blind or partially sighted (prevalence 0.41%). A total of 66 patients participated with ocular diseases of age-related macular degeneration 39 (59%), glaucoma 11 (17%), diabetic retinopathy two (3%), retinitis pigmentosa two (3%), and 12 (18%) 'others'. Better eye visual acuity was counting fingers or worse in 32 (48.5%). NEI-VFQ scores were poor-overall mean 41.5% (SD 23.5). In all, 80% had a social services home visit with one-third of these still in contact. In all, 66% had undergone a low vision aid assessment and 57.6% of these used their aid. The awareness and receipt of benefits arising from registration as visually impaired were lower than for other supportive measures available for reasons unrelated to vision. None had a guide dog. CONCLUSIONS: We found expected patterns of low vision but poorer levels of function and support that may reflect age and deprivation in a population failed by the current systems for identification, registration, and rehabilitation based on legislation overtaken by demographic change and social provision independent of visual status.

The high-level mobility assessment tool (HiMAT) for traumatic brain injury. Part 2: content validity and discriminability.

PRIMARY OBJECTIVES: (i) To assess the measurement properties of the high-level mobility assessment tool (HiMAT) for people with traumatic brain injury (TBI), (ii) to measure the extent to which the HiMAT is a uni-dimensional, discriminative hierarchical outcome scale. RESEARCH DESIGN: The content validity was assessed using a three-stage process of investigating internal consistency, factor analysis and Rasch analysis. The uni-dimensionality of the HiMAT items was also tested. Discriminability was investigated by correlating raw and logit scores obtained from Rasch analysis. The study was conducted at a major rehabilitation facility using a convenience sample of 103 adults with TBI. MAIN OUTCOMES AND RESULTS: The internal consistency for the high-level items was very high (Cronbach's alpha = 0.99). Principal axis factoring identified several balance items as belonging to a second factor not related to high-level mobility, hence these items were excluded. Rasch analysis identified several misfitting items, such as walking around a figure of eight and stopping from a run, which were also excluded. Logit scores were used to exclude clustered and, therefore, redundant items. Raw scores correlated very highly (r = 0.98) with logit scores, indicating that raw scores provided good discriminability and were suitable for use by clinicians. CONCLUSION: The HiMAT, which assesses higher-level mobility requirements of people with TBI for return to pre-accident social, leisure and sporting activities, is a uni-dimensional and discriminative scale for quantifying therapy outcomes.

High-power terahertz synchrotron sources.

Electromagnetic waves, or light, are produced by accelerating electrons according to the formula assigned the name of Sir Joseph Larmor, who was secretary of The Royal Society from 1901 to 1912. For relativistic electrons the emission is enhanced by the fourth power of the increase in mass. Thus for 10 MeV electrons, for which the mass increases by a factor of 21, the enhancement is a factor of 200000. We have generated high-power broadband THz light using relativistic electrons and demonstrated that ca. 100 W can readily be produced in a band from 0.1 to 3 THz with possible extensions to 6 THz. The experiments use a new generation of light source in which bunches of electrons circulate once, but in which their energy is recovered. In such a machine the electron bunches can be very much shorter than those, say, in storage rings or synchrotrons.

Very High Power THz Radiation Sources.

We report the production of high power (20watts average, ∼ 1 Megawatt peak) broadbandTHz light based on coherent emission fromrelativistic electrons. Such sources areideal for imaging, for high power damagestudies and for studies of non-linearphenomena in this spectral range. Wedescribe the source, presenting theoreticalcalculations and their experimentalverification. For clarity we compare thissource with one based on ultrafast lasertechniques.

Very high power THz radiation at Jefferson Lab.

We report the production of high power (20 W average, approximately 1 MW peak) broadband THz light based on coherent emission from relativistic electrons. We describe the source, presenting theoretical calculations and their experimental verification. For clarity we compare this source with that based on ultrafast laser techniques, and in fact the radiation has qualities closely analogous to those produced by such sources, namely that it is spatially coherent, and comprises short duration pulses with transform-limited spectral content. In contrast to conventional THz radiation, however, the intensity is many orders of magnitude greater due to the relativistic enhancement.

High-power terahertz radiation from relativistic electrons.

Terahertz (THz) radiation, which lies in the far-infrared region, is at the interface of electronics and photonics. Narrow-band THz radiation can be produced by free-electron lasers and fast diodes. Broadband THz radiation can be produced by thermal sources and, more recently, by table-top laser-driven sources and by short electron bunches in accelerators, but so far only with low power. Here we report calculations and measurements that confirm the production of high-power broadband THz radiation from subpicosecond electron bunches in an accelerator. The average power is nearly 20 watts, several orders of magnitude higher than any existing source, which could enable various new applications. In particular, many materials have distinct absorptive and dispersive properties in this spectral range, so that THz imaging could reveal interesting features. For example, it would be possible to image the distribution of specific proteins or water in tissue, or buried metal layers in semiconductors; the present source would allow full-field, real-time capture of such images. High peak and average power THz sources are also critical in driving new nonlinear phenomena and for pump-probe studies of dynamical properties of materials.

Profiling lipids across Caucasian and Afro-American hair transverse cuts, using synchrotron infrared microspectrometry.

Synchrotron-based infrared microscopic measurements have been performed on various hair transverse sections, sampled either from the heads of Caucasian or Afro-American subjects. Lipid content of various virgin hair transverse sections was established, with an unprecedented resolution. The variations in shape and intensity of the CH(2), CH(3), amide I and amide II bands, before and after lipid removal by solvent extraction, were profiled, showing clearly that Caucasian hair often contains lipids localized inside the medulla and to a lesser extent inside the cuticle. This statement does not hold for the Afro-American hair analysed. For this, the FT-IR spectra do not change within the hair section and are insensitive to solvent extraction. The importance of the origin of hair on its physical and chemical properties has to be taken into account in future investigations.

Highly resolved chemical imaging of living cells by using synchrotron infrared microspectrometry.

Using synchrotron radiation as an ultra-bright infrared source, we have been able to map the distributions of functional groups such as proteins, lipids, and nucleic acids inside a single living cell with a spatial resolution of a few microns. In particular, we have mapped the changes in the lipid and protein distributions in both the final stages of cell division and also during necrosis.

Chemical imaging of nucleic acids, proteins and lipids of a single living cell. Application of synchrotron infrared microspectrometry in cell biology.

Hybridoma B-cells have been used as models to evaluate the performance of synchrotron infrared microscopy to obtain chemical images of a single living cell. Chemical mapping of nucleic acids, proteins and lipids at a resolution of a few microns, close to the diffraction limit in the mid-infrared region are shown.